1. Field of the Invention
This invention relates to an efficient and scalable process for preparing 1,2,4- and 1,3,4-oxadiazole carboxylates from readily available starting materials.
2. Description of the Related Art
Oxadiazoles are widely used as ester and amide bioisosteres. They are also useful as antiviral agents, neuroprotectants, and anti-inflammatory agents. An object of the present invention is to develop an efficient, scalable, and cost effective procedure for preparing multigram quantities of 1,2,4- and 1,3,4-oxadiazole carboxylates from readily available starting materials.
1,2,4-Oxadiazoles can be prepared by condensing an amidoxime with an acid chloride or an acid anhydride. A limitation of this method is the availability of the starting amidoxime, which is usually prepared by treating a substituted oximyl chloride the highly toxic and caustic ammonia gas. This method also requires the use of expensive starting materials and cannot be used to generate a wide variety of 1,2,4-oxadiazoles. In addition, this procedure is not readily amenable to large scale synthesis.
1,3,4-Oxadiazoles have been prepared by making a diacylhydrazine and treating it with thionyl chloride and pyridine to form a 1,2,3,4-oxathiadiazole-S-oxide intermediate, which then thermally eliminates sulfur dioxide to yield the desired 1,3,4-oxadiazole. Borg, S., Estenne-Boutou, G., Luthman, K., Csoregh, I., Hesselink, W., U. B. J. Org. Chem., 1995, 60, 2112-2120. This methodology has several drawbacks. First, the procedure is extremely inefficient, affording yields of 6 to 30 percent. Second, it is not amenable to scale up. Finally, this method uses acidic dehydrating agents, which will destroy any acid labile groups. Next, the preparation of the diacylhydrazide requires the use of triethylamine, a very odiferous and relatively expensive base. The method also requires numerous expensive and time consuming chromatographic separations in order to obtain the pure desired product. Finally, many 1,3,4-oxadiazoles are acid labile and readily decompose when attempting to remove the BOC group with HCl.
Another key limitation of the prior art methods for producing the 1,2,4- and 1,3,4-oxadiazoles is that the tertiary-butoxy carbonyl (BOC) nitrogen-protecting group is left intact at the end of the synthesis. BOC groups are normally removed under acidic conditions in a protic solvent, such as dry hydrogen chloride in saturated methanol or trifluoroacetic acid in methanol. If these methods are used to remove the BOC group from the oxadiazole product, decomposition frequently occurs, particularly in the synthesis of 1,3,4-oxadiazole systems. The use of toxic HCl gas is also undesirable.
A safe and efficient procedure for the synthesis of 1,2,4- and 1,3,4-oxadiazoles is desired that is amenable to scale up, that affords increased yields, and that does not require: 1) the use of expensive, sensitive or highly toxic reagents; 2) the need for column chromatography; 3) and the use of harsh deprotection methods.